Diabetes Obes Metab. 2023 Oct 5. doi: 10.1111/dom.15288. Online ahead of print.

ABSTRACT

AIM: Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced β-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease β-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios.

MATERIALS AND METHODS: New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays.

RESULTS: First, we show that very substantial reductions in β-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics.

CONCLUSIONS: Completely abolishing β-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.

PMID:37795639 | DOI:10.1111/dom.15288

Front Oncol. 2023 Sep 15;13:1225081. doi: 10.3389/fonc.2023.1225081. eCollection 2023.

ABSTRACT

Immune checkpoints limit the activation of the immune system and serve an important homeostatic function but can also restrict immune responses against tumors. Inhibition of specific immune checkpoint proteins such as the B7:CD28 family members programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) has transformed the treatment of various cancers by promoting the anti-tumor activation of immune cells. In contrast to these effects, the V-domain immunoglobulin suppressor of T-cell activation (VISTA) regulates the steady state of the resting immune system and promotes homeostasis by mechanisms distinct from PD-1 and CTLA-4. The effects of VISTA blockade have been shown to include a decrease in myeloid suppression coupled with proinflammatory changes by mechanisms that are separate and distinct from other immune checkpoint proteins; in some preclinical studies these immune effects appear synergistic. Given the potential benefits of VISTA blockade in the context of cancer therapy, the second Annual VISTA Symposium was convened virtually on September 23, 2022, to review new research from investigators and immuno-oncology experts. Discussions in the meeting extended the knowledge of VISTA biology and the effects of VISTA inhibition, particularly on cells of the myeloid lineage and resting T cells, as three candidate anti-VISTA antibodies are in, or nearing, clinical development.

PMID:37795437 | PMC:PMC10547146 | DOI:10.3389/fonc.2023.1225081

Front Endocrinol (Lausanne). 2023 Sep 18;14:1287807. doi: 10.3389/fendo.2023.1287807. eCollection 2023.

NO ABSTRACT

PMID:37795358 | PMC:PMC10545849 | DOI:10.3389/fendo.2023.1287807

Front Pharmacol. 2023 Sep 19;14:1267294. doi: 10.3389/fphar.2023.1267294. eCollection 2023.

ABSTRACT

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals' genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current "one-size-fits-all" approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth.

PMID:37795032 | PMC:PMC10545970 | DOI:10.3389/fphar.2023.1267294

Methods Mol Biol. 2022;2547:C1. doi: 10.1007/978-1-0716-2573-6_22.

NO ABSTRACT

PMID:37794232 | DOI:10.1007/978-1-0716-2573-6_22

Fundam Clin Pharmacol. 2023 Oct 4. doi: 10.1111/fcp.12958. Online ahead of print.

ABSTRACT

BACKGROUND: Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (ABCG2 c.421C>A) of the breast cancer resistance protein.

METHODS: In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose-adjusted lamotrigine troughs at steady state were the outcome, and (iii) ABCG2 c.421C>A genotype (wild-type [wt] homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (UGT1A4*3 c.142T>G, rs2011425; UGT2B7-161C>T, rs7668258; ABCB1 1236C>T, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios [GMR]).

RESULTS: The two studies yielded consistent results (replicated); hence, we analyzed combined data (total N = 471, 140 treated, 331 controls, 378 ABCG2 c.421C>A wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, n = 21 vs. controls, n = 72) was around 60% higher than in wt subjects (treated, n = 119 vs. controls, n = 259)-ratio of GMRs 1.61 (95%CI 1.23-2.11) (frequentist) and 1.63 (95%CrI 1.26-2.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364 μmol/L vs. no valproate; or valproate ≥364 μmol/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low.

CONCLUSION: Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.

PMID:37793994 | DOI:10.1111/fcp.12958

Front Neurosci. 2023 Sep 8;17:1156362. doi: 10.3389/fnins.2023.1156362. eCollection 2023.

ABSTRACT

BACKGROUND: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.

METHODS: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.

RESULTS: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.

CONCLUSION: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

PMID:37790589 | PMC:PMC10542409 | DOI:10.3389/fnins.2023.1156362

J Antimicrob Chemother. 2023 Oct 4:dkad299. doi: 10.1093/jac/dkad299. Online ahead of print.

NO ABSTRACT

PMID:37788983 | DOI:10.1093/jac/dkad299

Drug Ther Bull. 2023 Oct 3:dtb-2023-000009. doi: 10.1136/dtb.2023.000009. Online ahead of print.

ABSTRACT

There is considerable interindividual variability in the effectiveness and safety of medicines. Although the reasons for this are multifactorial, it is well recognised that genetic changes impacting the absorption or metabolism of these drugs play a significant contributory role. Understanding how these pharmacogenetic variants impact response to medicines, and leveraging this knowledge to guide prescribing, could have significant benefits for patients and health services. This article provides an introduction to the field of pharmacogenetics, including its nomenclature, the existing evidence base and the current state of implementation globally. We discuss the challenges in translating pharmacogenetic research into clinical practice and highlight the considerable benefits which can emerge in those health services where implementation is successful.

PMID:37788890 | DOI:10.1136/dtb.2023.000009

Acta Med Port. 2023 Oct 2;36(10):689-690. doi: 10.20344/amp.20170. Epub 2023 Oct 2.

NO ABSTRACT

PMID:37788651 | DOI:10.20344/amp.20170

Biochem Biophys Res Commun. 2023 Sep 29;682:1-20. doi: 10.1016/j.bbrc.2023.09.064. Online ahead of print.

ABSTRACT

Metabolic disorders are increasingly prevalent worldwide, leading to high rates of morbidity and mortality. The variety of metabolic illnesses can be addressed through personalized medicine. The goal of personalized medicine is to give doctors the ability to anticipate the best course of treatment for patients with metabolic problems. By analyzing a patient's metabolomic, proteomic, genetic profile, and clinical data, physicians can identify relevant diagnostic, and predictive biomarkers and develop treatment plans and therapy for acute and chronic metabolic diseases. To achieve this goal, real-time modeling of clinical data and multiple omics is essential to pinpoint underlying biological mechanisms, risk factors, and possibly useful data to promote early diagnosis and prevention of complex diseases. Incorporating cutting-edge technologies like artificial intelligence and machine learning is crucial for consolidating diverse forms of data, examining multiple variables, establishing databases of clinical indicators to aid decision-making, and formulating ethical protocols to address concerns. This review article aims to explore the potential of personalized medicine utilizing omics approaches for the treatment of metabolic disorders. It focuses on the recent advancements in genomics, epigenomics, proteomics, metabolomics, and nutrigenomics, emphasizing their role in revolutionizing personalized medicine.

PMID:37788525 | DOI:10.1016/j.bbrc.2023.09.064

Annu Rev Pharmacol Toxicol. 2023 Oct 3. doi: 10.1146/annurev-pharmtox-022823-035521. Online ahead of print.

ABSTRACT

Anthracycline-induced cardiotoxicity (AIC) is a serious and common side effect of anthracycline therapy. Identification of genes and genetic variants associated with AIC risk has clinical potential as a cardiotoxicity predictive tool and to allow the development of personalized therapies. In this review, we provide an overview of the function of known AIC genes identified by association studies and categorize them based on their mechanistic implication in AIC. We also discuss the importance of functional validation of AIC-associated variants in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to advance the implementation of genetic predictive biomarkers. Finally, we review how patient-specific hiPSC-CMs can be used to identify novel patient-relevant functional targets and for the discovery of cardioprotectant drugs to prevent AIC. Implementation of functional validation and use of hiPSC-CMs for drug discovery will identify the next generation of highly effective and personalized cardioprotectants and accelerate the inclusion of approved AIC biomarkers into clinical practice. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37788492 | DOI:10.1146/annurev-pharmtox-022823-035521

Annu Rev Pharmacol Toxicol. 2023 Oct 3. doi: 10.1146/annurev-pharmtox-022323-082311. Online ahead of print.

ABSTRACT

I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored/coauthored more than 600 publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: (a) discovery and characterization of the AHR/CYP1 axis, (b) pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, (c) standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and (d) discovery and characterization of the SLC39A8 gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37788491 | DOI:10.1146/annurev-pharmtox-022323-082311

PLoS One. 2023 Oct 3;18(10):e0292131. doi: 10.1371/journal.pone.0292131. eCollection 2023.

ABSTRACT

Pharmacogenomic testing may be used to improve treatment outcomes and reduce the frequency of adverse drug reactions (ADRs). Population specific, targeted pharmacogenetics (PGx) panel-based testing methods enable sensitive, accurate and economical implementation of precision medicine. We evaluated the analytical performance of the GenoPharm® custom open array platform which evaluates 120 SNPs across 46 pharmacogenes. Using commercially available reference samples (Coriell Biorepository) and in-house extracted DNA, we assessed accuracy, precision, and linearity of GenoPharm®. We then used GenoPharm® on 218 samples from two Southern African black populations and determined allele and genotype frequencies for selected actionable variants. Across all assays, the GenoPharm® panel demonstrated 99.5% concordance with the Coriell reference samples, with 98.9% reproducibility. We observed high frequencies of key genetic variants in people of African ancestry: CYP2B6*6 (0.35), CYP2C9*8, *11 (0.13, 0.03), CYP2D6*17 (0.21) and *29 (0.11). GenoPharm® open array is therefore an accurate, reproducible and sensitive test that can be used for clinical pharmacogenetic testing and is inclusive of variants specific to the people of African ancestry.

PMID:37788265 | DOI:10.1371/journal.pone.0292131

Mol Biol Rep. 2023 Oct 3. doi: 10.1007/s11033-023-08748-z. Online ahead of print.

ABSTRACT

BACKGROUND: Analytical validity is a prerequisite to use a next generation sequencing (NGS)-based application as an in vitro diagnostic test or a companion diagnostic in clinical practice. Currently, in the United States and the European Union, the intended use of such NGS-based tests does not refer to guided drug therapy on the basis of pharmacogenetic profiling of drug metabolizing enzymes, although the value of pharmacogenetic testing has been reported. However, in research, a large variety of NGS-based tests are used and have been confirmed to be at least comparable to array-based testing.

METHODS AND RESULTS: A systematic evaluation was performed screening and assessing published literature on analytical validation of NGS applications for pharmacogenetic profiling of CYP2C9, CYP2C19, CYP2D6, VKORC1 and/or UGT1A1. Although NGS applications are also increasingly used for implementation assessments in clinical practice, we show in the present systematic literature evaluation that published information on the current status of analytical validation of NGS applications targeting drug metabolizing enzymes is scarce. Furthermore, a comprehensive performance evaluation of whole exome and whole genome sequencing with the intended use for pharmacogenetic profiling has not been published so far.

CONCLUSIONS: A standard in reporting on analytical validation of NGS-based tests is not in place yet. Therefore, many relevant performance criteria are not addressed in published literature. For an appropriate analytical validation of an NGS-based qualitative test for pharmacogenetic profiling at least accuracy, precision, limit of detection and specificity should be addressed to facilitate the implementation of such tests in clinical use.

PMID:37787843 | DOI:10.1007/s11033-023-08748-z

Neurotherapeutics. 2023 Oct 2. doi: 10.1007/s13311-023-01444-7. Online ahead of print.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1G93A mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.

PMID:37782409 | DOI:10.1007/s13311-023-01444-7

Front Pharmacol. 2023 Sep 14;14:1248898. doi: 10.3389/fphar.2023.1248898. eCollection 2023.

ABSTRACT

Introduction: Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD gene, is the rate-limiting enzyme responsible for fluoropyrimidine (FP) catabolism. DPYD gene variants seriously affect DPD activity and are well validated predictors of FP-associated toxicity. DPYD variants rs3918290, rs55886062, rs67376798, and rs75017182 are currently included in FP genetic-based dosing guidelines and are recommended for genotyping by the European Medicines Agency (EMA) before treatment initiation. In Greece, however, no data exist on DPYD genotyping. The aim of the present study was to analyze prevalence of DPYD rs3918290, rs55886062, rs67376798, rs75017182, and, additionally, rs1801160 variants, and assess their association with FP-induced toxicity in Greek cancer patients. Methods: Study group consisted of 313 FP-treated cancer patients. DPYD genotyping was conducted on QuantStudio ™ 12K Flex Real-Time PCR System (ThermoFisher Scientific) using the TaqMan® assays C__30633851_20 (rs3918290), C__11985548_10 (rs55886062), C__27530948_10 (rs67376798), C_104846637_10 (rs75017182) and C__11372171_10 (rs1801160). Results: Any grade toxicity (1-4) was recorded in 208 patients (66.5%). Out of them, 25 patients (12%) experienced grade 3-4 toxicity. DPYD EMA recommended variants were detected in 9 patients (2.9%), all experiencing toxicity (p = 0.031, 100% specificity). This frequency was found increased in grade 3-4 toxicity cases (12%, p = 0.004, 97.9% specificity). DPYD deficiency increased the odds of grade 3-4 toxicity (OR: 6.493, p = 0.014) and of grade 1-4 gastrointestinal (OR: 13.990, p = 0.014), neurological (OR: 4.134, p = 0.040) and nutrition/metabolism (OR: 4.821, p = 0.035) toxicities. FP dose intensity was significantly reduced in DPYD deficient patients (β = -0.060, p <0.001). DPYD rs1801160 variant was not associated with FP-induced toxicity or dose intensity. Triple interaction of DPYD*TYMS*MTHFR was associated with grade 3-4 toxicity (OR: 3.725, p = 0.007). Conclusion: Our findings confirm the clinical validity of DPYD reduced function alleles as risk factors for development of FP-associated toxicity in the Greek population. Pre-treatment DPYD genotyping should be implemented in clinical practice and guide FP dosing. DPYD*gene interactions merit further investigation as to their potential to increase the prognostic value of DPYD genotyping and improve safety of FP-based chemotherapy.

PMID:37781702 | PMC:PMC10536177 | DOI:10.3389/fphar.2023.1248898

Front Digit Health. 2023 Sep 15;5:1246659. doi: 10.3389/fdgth.2023.1246659. eCollection 2023.

ABSTRACT

Healthcare is increasingly fragmented, resulting in escalating costs, patient dissatisfaction, and sometimes adverse clinical outcomes. Strategies to decrease healthcare fragmentation are therefore attractive from payer and patient perspectives. In this commentary, a patient-centered smart phone application called Virtual Twin for Healthcare Management (VTHM) is proposed, including its organizational layout, basic functionality, and potential clinical applications. The platform features a virtual twin hub that displays the body and its health data. This is a physiologically based human model that is "virtualized" for the patient based on their unique genetic, molecular, physiological, and disease characteristics. The spokes of the system are a full service and interoperable electronic-health record, accessible to healthcare providers with permission on any device with internet access. Theoretical case studies based on real scenarios are presented to show how VTHM could potentially improve patient care and clinical efficiency. Challenges that must be overcome to turn VTHM into reality are also briefly outlined. Notably, the VTHM platform is designed to operationalize current and future precision medicine initiatives, such as access to molecular diagnostic results, pharmacogenomics-guided prescribing, and model-informed precision dosing.

PMID:37781454 | PMC:PMC10540783 | DOI:10.3389/fdgth.2023.1246659

Lancet Reg Health Southeast Asia. 2023 Sep 21;17:100281. doi: 10.1016/j.lansea.2023.100281. eCollection 2023 Oct.

ABSTRACT

BACKGROUND: Despite being the second least populated state, Mizoram exhibits the highest incidence rate of cancer in India. Its inhabitants, constituting an endogamous and isolated population, have embraced their own distinct culture, way of life and dietary preferences, setting them apart from the rest of mainland India. In 2003, the Mizoram Population Based Cancer Registry (PBCR) was established under the auspices of the National Centre for Disease Informatics and Research (NCDIR), a division of the Indian Council of Medical Research (ICMR), in collaboration with the Department of Health & Family Welfare of the Government of Mizoram, India.

METHODS: Cancer incidence and mortality data were extracted from the Mizoram PBCR spanning the years 2003-2020. The Age Standardized Incidence Rate (ASIR) and Age Standardized Mortality Rate (ASMR) were computed per 100,000 individuals, utilizing Segi's World Standard Population as the benchmark. The trajectory of these changes was analysed employing the Joinpoint Regression Analysis Program, Version 4.9.1.0.13, to unveil the Annual Percent Change (APC) with a 95% Confidence Interval and a Significance test (p < 0.05) using Monte Carlo Permutation. The resulting graphical visualizations were generated using Flourish Studio.15.

FINDINGS: The overall ASIR for all cancer sites among men was 197.2 per 100,000, while for women, it was 164.9 per 100,000. Among men, the most prevalent cancer site was the Stomach (ASIR = 41.4), followed by Head & Neck, Lung, Oesophagus, Colorectal, Liver, Urinary, Non-Hodgkin's Lymphoma and Prostate cancers. Conversely, among women, Lung cancer exhibited the highest incidence (ASIR = 26.7), succeeded by Cervical, Breast, Stomach, Head & Neck, Colorectal, Oesophagus, Liver and Ovarian cancers. Stomach cancer emerged as the leading cause of death among men (ASMR = 22.6) and among women, Lung cancer held the highest ASMR (15.9). Joinpoint regression analysis revealed a rising trend in incidence and mortality over time for overall cancer sites. Among the primary cancer sites contributing to incidence and mortality, an increase in APC was observable for all, except Stomach cancer, in both men and women. The diagnostic approach, except for cases of cancer with unknown primary sites, involved a microscopic method.

INTERPRETATION: This cross-sectional study examines PBCR reports spanning from 2003 to 2020, shedding light on a consistent uptick in cancer incidence and mortality trends in Mizoram. Stomach cancer emerges as the most prevalent and primary cause of cancer-related deaths among men, while Lung cancer takes a parallel role in women. The elevated cancer incidence and the growing trend among younger generations might stem from the static lifestyle and dietary patterns prevalent within the endogamous tribal population, potentially contributing to a genetic predisposition. The escalation in mortality rates could be attributed to a dearth of specialized diagnostic facilities and skilled human resources, treatment strategies guided by genomic research and transportation challenges. This underscores the urgent requirement for comprehensive scientific exploration across diverse facets. The implementation of easily accessible diagnostic facilities in proximity and genetic testing for pharmacogenomics to enhance prognoses would also aid in mitigating the burden and advancing the healthcare system's effectiveness.

FUNDING: Population Based Cancer Registry (PBCR) was supported by National Centre for Disease Informatics and Research (NCDIR) of the Indian Council of Medical Research (ICMR), India.

PMID:37780980 | PMC:PMC10541469 | DOI:10.1016/j.lansea.2023.100281

Pharmacol Ther. 2023 Sep 28:108540. doi: 10.1016/j.pharmthera.2023.108540. Online ahead of print.

ABSTRACT

Protein sulfoconjugation, or sulfation, represents a critical post-translational modification (PTM) process that involves the attachment of sulfate groups to various positions of substrates within the protein peptides or glycoproteins. This process plays a dynamic and complex role in many physiological and pathological processes. Here, we summarize the importance of sulfation in the fields of oncology, virology, drug-induced liver injury (DILI), inflammatory bowel disease (IBD), and atherosclerosis. In oncology, sulfation is involved in tumor initiation, progression, and migration. In virology, sulfation influences viral entry, replication, and host immune response. In DILI, sulfation is associated with the incidence of DILI, where altered sulfation affects drug metabolism and toxicity. In IBD, dysregulation of sulfation compromises mucosal barrier and immune response. In atherosclerosis, sulfation influences the development of atherosclerosis by modulating the accumulation of lipoprotein, and the inflammation, proliferation, and migration of smooth muscle cells. The current review underscores the importance of further research to unravel the underlying mechanisms and therapeutic potential of targeting sulfoconjugation in various diseases. A better understanding of sulfation could facilitate the emergence of innovative diagnostic or therapeutic strategies.

PMID:37777160 | DOI:10.1016/j.pharmthera.2023.108540